Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway
Open accessAbstract
The importance of gut microbiota in human health and pathophysiology is undisputable. Despite the abundance of metagenomics data, the functional dynamics of gut microbiota in human health and disease remain elusive. Urolithin A (UroA), a major microbial metabolite derived from polyphenolics of berries and pomegranate fruits displays anti-inflammatory, anti-oxidative, and anti-ageing activities. Here, we show that UroA and its potent synthetic analogue (UAS03) significantly enhance gut barrier function and inhibit unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. Importantly, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction in addition to anti-inflammatory activities. Cumulatively, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing inflammation to protect from colonic diseases.
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AhR-/- mice exhibit increased inflammation and severe colitis phenotypes compared with wild type mice in the TNBS- or DSS-induced colitis models.
“AhR–/– mice exhibit increased inflammation and severe colitis phenotypes compared with wild type mice in the 2,4,6-trinitrobenzene sulfonic acid (TNBS) or DSS-induced colitis models.22,96”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [22]
Levels of tight junction proteins in AhR-/- mice are significantly reduced compared with wild type mice leading to increased gut leakiness.
“Levels of TJ proteins in AhR–/– mice are also significantly reduced compared with wild type mice leading to increased gut leakiness.22”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [22]
Treatment with UroA significantly enhanced gut barrier integrity through upregulation of TJ proteins via an AhR-Nrf2-dependent pathway.
“Our group demonstrated that treatment with UroA significantly enhanced gut barrier integrity through upregulation of TJ proteins via an AhR-Nrf2–dependent pathway.22”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [22]
Treatment with UroA mitigated DSS- or TNBS-induced colitis in mice through enhancing gut barrier function and blocking the production of inflammatory cytokines.
“Importantly, treatment with UroA mitigated DSS- or TNBS-induced colitis in mice through enhancing gut barrier function and blocking the production of inflammatory cytokines.22”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [22]
UroA failed to upregulate TJ proteins such as Cldn4, ZO-1 and Ocln in AhR-/- and Nrf2-/- mice.
“UroA failed to upregulate TJ proteins such as Cldn4, ZO-1 and Ocln in AhR–/– and Nrf2–/– mice.”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [22]
UroA and UAS03 blocked unwarranted inflammation and mitigated colitis in pre-clinical models.
“Additionally, UroA and UAS03 also blocked unwarranted inflammation and mitigated colitis in pre-clinical models.22”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [22]
UroA and its synthetic structural analogue UAS03 enhanced gut barrier function via upregulation of TJ proteins such as CLDN-4, OCLN, and ZO-1.
“Our group showed that UroA and its synthetic structural analogue UAS03 enhanced gut barrier function via upregulation of TJ proteins such as CLDN-4, OCLN, and ZO-1.”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [22]
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- Authors
- Singh, R., Chandrashekharappa, S., Bodduluri, S. R., Baby, B. V., Hegde, B., Kotla, N. G., Hiwale, A. A., Saiyed, T., Patel, P., Vijay-Kumar, M., Langille, M. G. I., Douglas, G. M., Cheng, X., Rouchka, E. C., Waigel, S. J., Dryden, G. W., Alatassi, H., Zhang, H.-G., Haribabu, B., Vemula, P. K., & Jala, V. R.
- Affiliations
- University of Louisville (US)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Dalhousie University (CA)
- University of Toledo (US)
- Corresponding author
- Vemula, Praveen K.
- Jala, Venkatakrishna R.
- ORCID
- Singh, Rajbir
- Chandrashekharappa, Sandeep
- Bodduluri, Sobha R.
- Baby, Becca V.
- Hegde, Bindu
- Kotla, Niranjan G.
- Saiyed, Taslimarif
- Langille, Morgan G. I.
- Douglas, Gavin M.
- Cheng, Xi
- Rouchka, Eric C.
- Waigel, Sabine J.
- Dryden, Gerald W.
- Alatassi, Houda
- Zhang, Huang-Ge
- Haribabu, Bodduluri
- Vemula, Praveen K.
- Jala, Venkatakrishna R.
- Venue
- Nature Communications
- Published
- 2019-01-09
- Volume
- 10
- Issue
- 1
- Pages
- 89-89
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6327034
- OpenAlex
- W2910159017
- Cited by
- 713
- References
- 69
- Citations by year
- 2026: 78 · 2025: 112 · 2024: 100 · 2023: 96 · 2022: 124 · 2021: 95 · 2020: 70 · 2019: 37
- FWCI
- 26.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Kentucky IDeA Networks of Biomedical Research Excellence (P20GM103436)
- Department of Biotechnology, Ministry of Science and Technology, India
- Department of Science and Technology, Ministry of Science and Technology, India
- National Institutes of Health (NIH P20GM103436)
- National Centre for Biological Sciences
- National Cancer Institute (CA191683, R21CA216090, R21CA191683)
- National Institute of General Medical Sciences (P30GM106396, P20GM125504, P20GM103436)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Nursing › Nutrition and Dietetics › Pomegranate: compositions and health benefits
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- urolithin A, intestinal barrier integrity, Nrf2 signaling, aryl hydrocarbon receptor, tight junction proteins, gut microbiota metabolites, colitis, intestinal inflammation, pomegranate polyphenols, colonic epithelium
- MeSH terms
- Animals, Coumarins, Epithelial Cells, Gene Expression Regulation, Humans, Intestinal Mucosa, Macrophages, Mice, Inbred C57BL, Specific Pathogen-Free Organisms, Receptors, Aryl Hydrocarbon, Mice, Knockout, Caco-2 Cells, HT29 Cells, NF-E2-Related Factor 2, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Tight Junction Proteins
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